Effects of Serum Aspartate Aminotransferase Levels in Patients With Autoimmune Hepatitis Influence Disease Course and Outcome

doi:10.1016/j.cgh.2008.08.018

Clinical Gastroenterology and Hepatology

Volume 6, Issue 12, December 2008, Pages 1389-1395

https://doi.org/10.1016/j.cgh.2008.08.018 Get rights and content

Background & Aims

Untreated patients with autoimmune hepatitis (AIH) who present with aspartate aminotransferase (AST) levels that are more than 5-fold greater than the upper limit of normal (UPLN) have a mortality rate of up to 80%. This study evaluated whether serum AST levels of patients, determined at presentation, are associated with disease course or outcome.

Methods

The records of 235 patients (median age, 46 y; range, 5–80 y) who presented with AIH, based on International AIH Group score (median, 22; range, 16–28), between 1970 and 2005, were examined. AST levels at presentation were available for 213 patients, who were assigned to 3 groups: group 1, AST less than 2× the UPLN, n = 26 (median, 62 IU; range, 23–97 IU); group 2, AST 2 to 10× the UPLN, n = 71 (median, 241 IU; range, 107–500 IU); and group 3, AST greater than 10× the UPLN, n = 116 (median, 1073 IU; range, 563–4603 IU).

Results

Patients in groups 1 and 2 had a significantly worse outcome (risk of liver transplantation or death) compared with those in group 3 (60% survival vs 82%; P = .01; odds ratio, 2.1). These patients were more likely to present with ascites (P < .001), hematemesis (P = .009), and cirrhosis or advanced fibrosis based on an index biopsy (P < .001). Patients in groups 1 and 2 also had lower bilirubin levels at presentation (P < .001) and were less likely to be symptomatic (P < .001).

Conclusions

In patients with AIH, AST levels greater than 10× the UPLN at presentation were associated with a lower risk of cirrhosis and a better long-term outcome than those with AST levels that were less than 10× the UPLN.

Section snippets

Patients

The records of 235 patients with definite AIH, classified according to the revised criteria of the International AIH Group (IAIHG) (median IAIHG score, 22; range, 16–28),⁴ presenting in adult hepatology clinics between 1971 and 2005, were examined retrospectively. All patients were seronegative for viral hepatitis as determined by tests for hepatitis B surface antigen and hepatitis C virus antibody, including retrospective testing for anti–hepatitis C virus of stored sera from patients who

Demographics and Biochemical Parameters

Patient demographics are summarized in Table 1. Age at diagnosis, sex distribution, and duration of follow-up period were not significantly different between the 3 groups. Patients with an AST level of less than 10× UPLN at presentation were significantly more likely to be asymptomatic (P < .001) and took significantly longer to be diagnosed with AIH than patients presenting with an AST level of greater than 10× UPLN (median time to diagnosis in groups 1 and 2, 6 mo; vs median time to diagnosis

Discussion

Serum aminotransferase activity at presentation represents an important marker of inflammation in patients with AIH. In this study we have investigated the long-term outcome of patients who present with different levels of increases in AST and identified that an AST level less than 10 times the UPLN at presentation was associated with reduced long-term survival, and, in addition, this group of patients presented more frequently with clinical and histologic evidence of cirrhosis. Moreover,

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Cited by (36)

Aminotransferases During Treatment Predict Long-Term Survival in Patients With Autoimmune Hepatitis Type 1: A Landmark Analysis
2022, Clinical Gastroenterology and Hepatology
Citation Excerpt :
In the current study a doubling of AST at diagnosis resulted in 27% decrease in HR. Patients with high levels of aminotransferases at diagnosis more often have symptoms and less often have decompensated cirrhosis.28 The increased rate of symptoms could lead to earlier diagnosis and treatment.
Biochemical remission, important treatment goal in autoimmune hepatitis (AIH), has been associated with better long-term survival. The aim of this study was to determine the independent prognostic value of aminotransferases and immunoglobulin G (IgG) during treatment on long-term transplant-free survival in AIH.
In a multicenter cohort alanine aminotransferase, aspartate aminotransferase (AST), and IgG were collected at diagnosis and 6, 12, 24, and 36 months after start of therapy and related to long-term outcome using Kaplan-Meier survival and Cox regression analysis with landmark analysis at these time points, excluding patients with follow-up ending before each landmark.
A total of 301 AIH patients with a median follow-up of 99 (range, 7–438) months were included. During follow-up, 15 patients required liver transplantation and 33 patients died. Higher AST at 12 months was associated with worse survival (hazard ratio [HR], 1.86; P < .001), while IgG was not associated with survival (HR, 1.30; P = .53). In multivariate analysis AST at 12 months (HR, 2.13; P < .001) was predictive for survival independent of age, AST at diagnosis and cirrhosis. Multivariate analysis for AST yielded similar results at 6 months (HR, 2.61; P = .001), 24 months (HR, 2.93; P = .003), and 36 months (HR, 3.03; P = .010). There was a trend toward a worse survival in patients with mildly elevated aminotransferases (1–1.5× upper limit of normal) compared with patients with normal aminotransferases (P = .097).
Low aminotransferases during treatment are associated with a better long-term survival in autoimmune hepatitis. IgG was not associated with survival in first 12 months of treatment. Normalization of aminotransferases should be the treatment goal for autoimmune hepatitis to improve long-term survival.
B-cell activating factor and IL-21 levels predict treatment response in autoimmune hepatitis
2022, JHEP Reports
Citation Excerpt :
Patients with high BAFF had the best treatment response with the highest remission rate and the lowest level of aminotransferases at 12 months. Previously high aminotransferases at diagnosis were reported to be correlated with a better long-term survival.20 Fast decrease of aminotransferases during treatment and complete biochemical remission at 12 months were also associated with a better long-term survival.21
Increased serum IgG and autoantibodies suggest involvement of B cells in autoimmune hepatitis (AIH). The aim of this study was to assess levels of B cell activating factor of the tumour necrosis family (BAFF), IL-21, and circulating B cell populations in AIH and correlate these to treatment response.
BAFF and IL-21 levels were determined in 66 patients with AIH before treatment and 10 healthy controls. Flow cytometry was performed on circulating B cells of 10 patients with AIH and 12 healthy controls.
Based on BAFF and IL-21 levels, untreated patients with AIH were divided into 3 groups: 27 (41%) patients with normal BAFF and IL-21 (normal BAFF), 27 (41%) patients with elevated BAFF but normal IL-21 (high BAFF), and 12 (18%) patients with elevated IL-21 (high IL-21). The high BAFF group presented with higher bilirubin compared with the normal BAFF and high IL-21 groups (159 vs. 26 vs. 89 μmol/L; p = 0.001; Mann–Whitney U test). After 12 months of treatment, 54% of the high BAFF group reached remission compared with 34% of the normal BAFF group and 0% of the high IL-21 group (p = 0.006, Chi-square test). During follow-up, 3 patients (25%) with high IL-21 developed primary sclerosing cholangitis (PSC) variant syndrome. Autoimmune-associated B cells were increased in patients with AIH compared with healthy controls (4.4 vs. 1.4%; p = 0.003, Mann–Whitney U test). BAFF levels were correlated positively with naïve B cells (p = 0.01) and negatively with class-switched B cells (p = 0.003) and nonclass-switched B cells (p = 0.005, Spearman correlation).
Using BAFF and IL-21, we identified different immunological phenotypes of AIH with a different presentation, treatment response, and outcome. Patients with high IL-21 had the poorest treatment response and a risk of developing PSC variant syndrome. BAFF level was related to shifts in circulating B-cell populations.
In patients with untreated autoimmune hepatitis (AIH), circulating B-cell activating factor of the tumour necrosis family (BAFF), IL-21, and B-cell populations were determined. Three subgroups were identified: with (1) normal BAFF and IL-21, (2) elevated BAFF and normal IL-21, and (3) elevated IL-21. Remission after 1-year treatment occurred in 54, 34, and 0% in Groups 1, 2, and 3, respectively. Group 2 had higher bilirubin, indicating more liver dysfunction. In 25% of patients with high IL-21, AIH-PSC variant syndrome developed, but none in the other groups. Autoimmune-associated B cells were elevated and BAFF levels correlated with certain B cells.
Non-invasive diagnosis and follow-up of autoimmune hepatitis
2022, Clinics and Research in Hepatology and Gastroenterology
Autoimmune hepatitis (AIH) is a liver disease characterised by necrotico-inflammatory lesions of hepatocytes, the presence of specific autoantibodies and response to corticosteroid treatment. AIH must be considered in any patient with acute or chronic liver disease. As there is no pathognomonic sign of AIH, the diagnosis is based on a combination of clinical, biological, immunological and histological findings, after excluding other causes of liver disease. The clinical and biological presentation of AIH is variable and AIH can be associated with an autoimmune biliary disease, primary biliary cholangitis or primary sclerosing cholangitis in an overlap syndrome. For these reasons, diagnosis of AIH can be challenging. Even if liver histology remains essential in the diagnosis of AIH, non-invasive tests can be used at different steps of the management of AIH: diagnosis of AIH, notably diagnosis of an overlap syndrome, assessment of severity of AIH, searching for extra-hepatic disease frequently associated to AIH, evaluation of response to therapy, decision of treatment withdrawal. This review aims to provide practical guidelines for the use of non-invasive tests for the diagnosis and the follow-up of AIH.
Rapid Response to Treatment of Autoimmune Hepatitis Associated With Remission at 6 and 12 Months
2020, Clinical Gastroenterology and Hepatology
Citation Excerpt :
However, the concept of rapidity of treatment response and its consequences has been largely unexplored. Results of our study accord with those of The King’s College group who described an association between baseline AST levels and cirrhosis development and long-term outcome.5 Patients with AST levels at diagnosis less than 10 times ULN had a higher risk on liver transplantation or death.
Changes in serum levels of transaminases immediately after initiation of treatment for autoimmune hepatitis (AIH) might be associated with biochemical markers of remission and liver-related events. We assessed the outcomes of patients with vs without rapid response to treatment of AIH in a large international cohort.
We performed a retrospective cohort study, collecting data from 2 independent cohorts of adults with AIH from 12 centers in 7 countries in Europe. We collected information on patient demographics; serologic, histologic, and biochemical analyses; and treatment. We used a receiver operating characteristic curve and Youden index to calculate the optimal percentage decrease in level of aspartate aminotransferase (AST) after 8 weeks of treatment that associated with normalization of transaminase levels after 26 weeks of treatment with predniso(lo)ne (primary outcome) in the first (discovery) cohort (n = 370). We evaluated the results in the second (validation) cohort (n = 370). Secondary outcomes were liver-related death or transplantation. We performed univariate and multivariable logistic and Cox regression with correction for confounders.
A significant decrease in level of AST after 8 weeks of treatment was significantly associated with normalization of transaminase levels at 26 and 52 weeks (P < .001); a decrease of more than 80% in level of AST was associated with optimal normalization. In both cohorts, rapid responders (≥80% decrease in level of AST after 8 weeks) were more likely to achieve normalization of transaminases at 26 and 52 weeks when compared to non-rapid responders. Rapid responders in the discovery cohort had lower risk of liver-related death or transplantation (adjusted hazard ratio 0.18; 95% CI 0.05–0.63; P = .007), although this was not confirmed in the validation cohort. Results from measurement of alanine aminotransferase did not differ significantly from those of AST for the primary outcome. Slow responders (without normalization of transaminases after 1 year) had the highest risk of liver transplantation or liver-related death.
In a retrospective study of patients with AIH, we found that a rapid response to treatment, based on level of AST after 8 weeks, associates with normalization of transaminase levels in the following year. Patients with a rapid response also have a lower risk of liver-related death or transplantation than patients without this rapid response.
The management of childhood liver diseases in adulthood
2017, Journal of Hepatology
Citation Excerpt :
The remaining patients often present insidiously, with more subtle symptoms of weight loss, anorexia, malaise occurring over many years. The presentation in adults is similar and varies from mild biochemical abnormalities to sub-acute liver failure [93]. Differences in autoimmune liver disease between children and adults is summarised in Table 5.
An increasing number of patients with childhood liver disease survive into adulthood. These young adults are now entering adult services and require ongoing management. Aetiologies can be divided into liver diseases that develop in young adults which present to adult hepatologists i.e., biliary atresia and Alagille syndrome or liver diseases that occur in children/adolescents and adults i.e., autoimmune hepatitis or Wilson’s disease. To successfully manage these young adults, a dynamic and responsive transition service is essential. In this review, we aim to describe the successful components of a transition service highlighting the importance of self-management support and a multi-disciplinary approach. We will also review some of the liver specific aetiologies which are unique to young adults, offering an update on pathogenesis, management and outcomes.
Prognosis of acute severe autoimmune hepatitis (AS-AIH): The role of corticosteroids in modifying outcome
2014, Journal of Hepatology
Citation Excerpt :
In addition the absence of chronic liver disease on histological evaluation was a pre-requisite for a diagnosis of AS-AIH. The serum level of AST was not used as a marker of disease severity in this cohort as previous work from this institution has shown that those with a higher AST have a better prognosis [18] and also that, in acute disease, the early fall in AST post treatment does not adequately predict treatment responsiveness [19]. The model for end stage liver disease (MELD) score was originally developed to predict poor outcomes following trans-jugular intra-hepatic porto-systemic shunts (TIPSS) [20].
No standardised definition exists for acute, severe AIH (AS-AIH). However, rapid identification of AS-AIH and early corticosteroid therapy may prevent the need for liver transplantation (LT). We set out to determine the clinical outcomes of patients with AS-AIH presenting to our institution with particular focus on the role of corticosteroids.
Retrospective analysis of a prospectively collated database identified patients presenting with AS-AIH from 1999 to 2009. We defined AS-AIH as an acute presentation with an INR of ⩾1.5 at any time without histological evidence of cirrhosis.
32 patients were identified with AS-AIH. Among the 32 AS-AIH patients 23 were treated with corticosteroids of whom 10 (48%) required LT, whilst all 9 untreated patients required LT (p = 0.01). Untreated patients demonstrated higher MELD scores at presentation (34 vs. 28 p = 0.01) and a non-significant decrease in episodes of sepsis but no difference in sepsis or mortality was observed between untreated or treated patients (11% vs. 26% p = 0.6 and 22% vs. 17% p = 0.99 respectively). Among treated patients, no difference in MELD scores was observed between responders or failures. Despite 59% undergoing LT, six deaths (19%) occurred.
In a well characterised cohort of patients with AS-AIH, almost 60% required LT and 20% died. There was no difference in prognostic scores between steroid responders and failures and steroid exposure did not appear to jeopardise survival. Patients with AS-AIH should be considered for a trial of corticosteroids expediently whilst a thorough search for sepsis and assessment for LT should occur if clinical deterioration or encephalopathy develops.

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: The authors disclose no conflicts.

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Original article—liver, pancreas, and biliary tractEffects of Serum Aspartate Aminotransferase Levels in Patients With Autoimmune Hepatitis Influence Disease Course and Outcome

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients

Demographics and Biochemical Parameters

Discussion

J Hepatol

Hepatology

Gastroenterology

Hepatology

Gastroenterology

J Autoimmun

Hepatology

Gastroenterology

Meeting report: International Autoimmune Hepatitis Group

Hepatology

Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features

Clin Liver Dis

Original article—liver, pancreas, and biliary tract
Effects of Serum Aspartate Aminotransferase Levels in Patients With Autoimmune Hepatitis Influence Disease Course and Outcome